Drug coating providing high drug loading

ABSTRACT

Aqueous drug coatings including at least one insoluble drug, wherein the insoluble drug accounts for about 85 wt % to about 97 wt % of the drug coatings are described. Such drug coatings may include only one insoluble drug, two or more insoluble drugs, or one or more insoluble drugs in combination with one or more soluble drugs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Patent applicationNo. 60/506,195, filed Sep. 26, 2003, which is incorporated herein byreference.

BACKGROUND

1. Field of the Invention

The present invention relates to drug coatings that can be formed withinor over dosage forms to deliver one or more insoluble or soluble drugs.In particular, the present invention provides drug coatings, coatingformulations and methods that provide aqueous-based drug coatings thatexhibit high loading of at least one insoluble drug, can be loaded withone or more insoluble drugs in combination with one or more insolubledrugs, and may be applied to a variety of different dosage forms.

2. State of the Art

Drug coatings are known in the art. For example, U.S. Pat. Nos.4,576,604, 4,717,569, 4,763,405, 5,273,760, 5,286,493, 5,407,686,5,998,478, 6,004,582 and 6,136,345, the contents of each of which areincorporated herein in their entirety by reference, teach variousdifferent drug coating formulations designed to provide the immediaterelease of one or more drugs of interest. In addition, InternationalApplications numbered WO 96/10996, WO 99/55313, WO 00/35426 and WO01/51038, the contents of which are incorporated herein in theirentirety by reference, also teach various different drug coatingformulations that may be provided over various different dosage forms.Drug coatings that can be coated over dosage forms are useful for avariety of reasons. In particular, the use of a drug-containing overcoatcan impart multiple performance characteristics to a single dosage form.For example, a dosage form providing the controlled release of one ormore drugs can be coated with an immediate release drug overcoat toprovide a dosage form that combines the benefits of an immediate releasedosage form with the benefits of a controlled release dosage form.

Where a coating formulation is to be used to provide a drug coating overor within a dosage form, the coating formulation should provide drugloading characteristics that permit therapeutic dosing of the drugincorporated in the coating, while maintaining desirable coatingcharacteristics. The loading characteristics of a drug coating becomeespecially important as the desired dose of drug to be delivered fromthe drug coating increases. As the required dose increases, the drugloading performance of the drug coating formulation must also increase.If the drug coating formulation does not exhibit sufficient drugloading, the thickness of a coating required to deliver a desired doseof drug may increase to such an extent that manufacturing, cosmetic, andpatient compliance issues may be encountered.

Moreover, although, drug coatings can be prepared from organic solventsor solvent systems containing one or more organic solvents, the use oforganic solvents presents several potential disadvantages. Organicsolvents are relatively costly, often volatile, are potentially harmfulto the environment, and create potential health hazards for workers.Because of the potential harm organic solvents present to workers andthe environment, the use of organic solvents in a manufacturing processtypically creates various regulatory hurdles that must be overcome.Moreover, where organic solvents are used to produce drug coatings, someresidual amount of solvent may remain in the finished coating, which,depending on the amount and the solvent used, may be harmful to anintended subject. In light of the potential disadvantages presented byorganic solvents, it is generally preferred to formulate drug coatingsand coating compositions using solvents or solvent systems that do notinclude organic solvents.

In particular, where possible, it is typically preferable to formulatedrug coatings using an aqueous solvent, such as purified water. It wouldbe desirable, therefore, to provide a drug coating that not only can becoated from an aqueous coating composition, but also exhibits drugloading capabilities that facilitate delivery of a wide range of drugdoses from coatings having physical and aesthetic characteristicssuitable for commercial production. Ideally, such a drug coatings couldbe formulated to include high concentrations of even water insolubledrugs, or combinations of one or more water insoluble drugs with one ormore water soluble drugs.

SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to an aqueous drugcoating. As it is used herein, the term “aqueous drug coating” refers toa water soluble or water erodible coating formed from a coatingformulation that is free from organic solvent. A drug coating accordingto the present invention can be created from an aqueous coatingformulation and includes at least one insoluble drug and a film-formingagent. As they are used herein, the term “drug” includes medicines,active agents, therapeutic compounds, therapeutic proteins, therapeuticpeptides, nutrients, vitamins, food supplements, and any other agentsthat are beneficial to an intended subject, the term “insoluble”indicates drugs having a solubility in water that is less than 50 mg/mlat 25° C., with drugs having a solubility in water of 8-10 mg/ml at 25°C. being preferred, and drugs having a solubility in water of less than1 mg/ml at 25° C. being particularly preferred. The drug coatingaccording to the present invention includes from about 85 wt % to about97 wt % drug, with preferred embodiments providing a drug loading ofabout 90 wt % to about 93 wt %.

Though each embodiment of the drug coating of the present inventionincludes at least one insoluble drug, the drug coating of the presentinvention is also embodied by drug coatings that include two or moreinsoluble drugs or one or more insoluble drugs in combination with oneor more soluble drugs. As it is used herein, the term “soluble”indicates drugs having a solubility in water that is 50 mg/ml or greaterat 25° C. Where the drug coating of the present invention includes morethan one drug, the different drugs may be included in the drug coatingat a ratio that provides a desired therapeutic effect. Moreover, theformulation of a drug coating of the present invention not only allowsthe loading of two or more drugs have different solubilities, butfollowing administration to an environment of operation, a drug coatingof the present invention permits proportional delivery of the two ormore drugs included therein.

In another embodiment, the drug coating according to the presentinvention includes a viscosity enhancer. As it is used herein, the term“viscosity enhancer” refers to a material that can be included in acomposition for forming a drug coating of the present invention that isboth water soluble and works to increase the viscosity of the coatingcomposition. Depending on the relative amounts and nature of the filmforming agent and the one or more drugs included in a drug coating ofthe present invention, incorporation of a viscosity enhancer in a drugcoating according to the present invention may better facilitateproduction of a drug coating that exhibits substantially uniformdistribution of drug.

In further embodiments, the drug coating of the present invention mayalso include a surfactant or a disintegrating agent. The term“surfactant” refers to material that is works to reduce the surfacetension of aqueous liquids such that an aqueous liquid can more easilyspread across and penetrate the materials forming a drug coatingaccording to the present invention, and the term “disintegrating agent”refers to a water swellable material that works to structurallycompromise a coating of the present invention as the disintegratingagent absorbs water and swells. In each embodiment, the drug coatingaccording to the present invention provides relatively high drugloading, and in each embodiment, the drug coating according to thepresent invention includes at least one insoluble drug. Therefore, asurfactant or disintegrating agent may be included in a drug coating ofthe present invention to facilitate break down or dissolution of thedrug coating after administration to an environment of operation andthereby increase the rate at which the drug included in the drug coatingis released.

In another aspect the, the present invention is directed to a drugcoating formulation. A coating formulation according to the presentinvention is an aqueous composition, preferably formed using purifiedwater as the solvent. The coating composition of the present inventionis formulated to allow coating of a drug coating according to thepresent invention, and in each embodiment, the coating formulation ofthe present invention includes at least one insoluble drug. As thecoating formulation of the present invention is an aqueous formulationthat includes at least one insoluble drug, the coating formulation ofthe present invention will typically be formed as a dispersion, withcoating formulations exhibiting a substantially uniform dispersion ofinsoluble drug being preferred. The coating composition according to thepresent invention may be formulated to facilitate spray coating of adrug coating of the present invention, and typically includes a solidscontent ranging up to 30 wt %, with coating compositions having a solidscontent ranging from about 5 wt % to about 25 wt % being preferred, andcoating compositions having a solids content ranging from about 10 wt %to about 20 wt % being particularly preferred.

In yet another aspect, the present invention is directed to a dosageform. A dosage form according to the present invention includes or iscoated with a drug coating according to the present invention. Inparticular, a dosage form according to the present invention includes acore coated by a drug coating of the present invention. The coreincluded in a dosage form according to the present invention can beformed using any material or device suitable for administration to anintended subject. For example, the core included in a dosage form of thepresent invention may includes a pill, a tablet or a capsule, and inpreferred embodiments the pill, tablet or capsule included in the coreis configured or formulated to provided controlled release of one ormore drugs. Where the dosage form of the present invention includes acore the provides controlled release of one or more drugs, the dosageform according to the present invention can be configured and formulatedto provide the combined benefits of an immediate release dosage form anda controlled release dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a graph illustrating the dissolution rate ofacetaminophen (APAP) from a drug coating according to the presentinvention compared to the dissolution rate of APAP from a commerciallyavailable Vicodin® tablet.

FIG. 2 provides a graph illustrating the dissolution rate of hydrocodonebitartrate (HBH) from a drug coating according to the present inventioncompared to the dissolution rate of HBH from a commercially availableVicodin® tablet.

FIG. 3 provides a graph illustrating the ratio of APAP to HBH releasedfrom drug coatings according to the present invention, where the releaseratio is determined by evaluating the dissolution profiles of APAP andHBH based on mass balance.

FIG. 4 provides a graph illustrating the dissolution rate of APAP fromtwo different drug coatings according to the present invention comparedto the dissolution rate of APAP from a commercially available NORCO®tablet.

FIG. 5 provides a graph illustrating the dissolution rate of APAP fromthree different drug coatings according to the present inventioncompared to the dissolution rate of APAP from a commercially availableNORCO® tablet.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention is directed to an aqueous drugcoating. A drug coating according to the present invention can be formedfrom an aqueous coating formulation and includes an insoluble drug and awater soluble, film-forming agent. Though each embodiment of a drugcoating according to the present invention includes an insoluble drug, adrug coating according to the present invention may also include aninsoluble drug in combination with a soluble drug. Moreover, a drugcoating according to the present invention may incorporate, for example,two or more insoluble drugs, an insoluble drug in combination with oneor more soluble drugs, or two or more insoluble drugs in combinationwith one or more soluble drugs. The total amount of drug included in adrug coating according to the present invention ranges from about 85 wt% to about 97 wt %, and in preferred embodiments, the total amount ofdrug included in a drug coating of the present invention ranges fromabout 90 wt % to about 93 wt %.

Even where the drug coating of the present invention includes onlyinsoluble drug material, the one or more insoluble drugs can account forup to about 97 wt % of the drug coating. In preferred embodiments, thedrug coating of the present invention includes from about 85 wt % toabout 97 wt % insoluble drug, with coatings exhibiting an insoluble drugloading of about 90 wt % to about 93 wt % being particularly preferred.If two or more insoluble drugs are included in a drug coating accordingto the present invention, the relative amounts of each insoluble drugcan vary, depending on the nature of the insoluble drugs used. Moreover,the relative amounts of two or more insoluble drugs included in a drugcoating according to the present invention can be adjusted, asnecessary, to achieve a desired therapeutic effect.

Where a drug coating according to the present invention includes one ormore insoluble drugs in combination with one or more soluble drugs, therelative amounts of the soluble and insoluble drugs included in thecoating can vary, depending on the nature of the drug materials, and canbe adjusted to achieve a desired therapeutic effect. The total amount ofsoluble drug included in a drug coating according to the presentinvention that incorporates both soluble and insoluble drugs preferablyranges from about 0.01 wt % to about 25 wt %, with drug coatingsincluding about 0.5 wt % to about 15 wt % soluble drug being morepreferred, and drug coatings including about 1 wt % to about 3 wt %soluble drug being most preferred. The total amount of insoluble drugincluded in a drug coating according to the present invention thatincorporates both soluble and insoluble drugs preferably ranges fromabout 60 wt % to about 96.99 wt %, with drug coatings including about 75wt % to about 89.5 wt % insoluble drug being more preferred, and drugcoatings including about 89 wt % to about 90 wt % insoluble drug beingmost preferred.

A wide range of insoluble drugs may be incorporated into a drug coatingaccording to the present invention. In one embodiment, the insolubledrug included in a drug coating according to the present invention maybe a non-steroidal anti-inflammatory drug, with acetaminophen oribuprofen being particularly preferred insoluble drugs. Preferably, theinsoluble drug included in a drug coating of the present inventionexhibits solubility characteristics similar those of acetaminophen at25° C. or to those of ibuprofen at 25° C.

A variety of different soluble drugs can also be used to create a drugcoating according to the present invention. In one embodiment, thesoluble drug included in a drug coating according to the presentinvention is an opioid drug, with hydrocodone, oxycodone, hydromorphone,oxymorphone, and methadone being particularly preferred soluble drugs.Where the drug coating of the present invention includes a soluble drug,the soluble drug included in the drug coating preferably exhibitssolubility that is at least as great as that of hydrocodone bitartrateat 25° C.

The film-forming agent included in a drug coating according to thepresent invention is water soluble and accounts for about 3 wt % toabout 15 wt % of the drug coating, with drug coatings having about 7 wt% to about 10 wt % film-forming agent being preferred. The film-formingagent included in a drug coating according to the present invention iswater soluble and preferably works to solubilize insoluble drug includedin the drug coating. In addition, the film-forming agent included in adrug coating according to the present invention may be chosen such thatthe film-forming agent forms a solid solution with one or more insolubledrugs included in the drug coating. It is believed that drug loading andfilm forming characteristics of a drug coating according to the presentinvention are enhanced by selecting a film-forming agent that forms asolid solution with at least one of the one or more insoluble drugsincluded in the drug coating. A drug dissolved at the molecular levelwithin the film-forming agent (a solid solution) is also expected to bemore readily bioavailable because, as the drug coating breaks down ordissolves, the drug is released into the gastrointestinal tract andpresented to the gastrointestinal mucosal tissue as discrete molecules.

In a preferred embodiment, the film-forming agent included in drugcoating according to the present invention is a film-forming polymer ora polymer blend including at least one film-forming polymer. Polymermaterials used as the film-forming agent of a drug coating of thepresent invention are water soluble. Examples of water soluble polymermaterials that may be used as the film-forming polymer of a drug coatingaccording to the present invention include, but are not limited to,hydroxypropylmethyl cellulose (“HPMC”), low molecular weight HPMC,hydroxypropyl cellulose (“HPC”) (e.g., Klucel®), hydroxyethyl cellulose(“HEC”) (e.g., Natrasol®), copovidone (e.g., Kollidon® VA 64), andPVA-PEG graft copolymer (e.g., Kollicoat® IR), and combinations thereof.A polymer blend or mixture may be used as the film forming agent of thepresent invention in order to achieve a drug coating havingcharacteristics that may not be achievable using a single film-formingpolymer in combination with the drug or drugs to be included in the drugcoating. For example, blends of HPMC and copovidone provide afilm-forming agent that allows the formation of drug coatings that notonly exhibit desirable drug loading characteristics, but also providecoatings that are aesthetically pleasing and exhibit desirable physicalproperties.

A drug coating according to the present invention may also include aviscosity enhancer. Because the drug coating of the present invention isan aqueous coating that includes one or more insoluble drugs, the drugcoating of the present invention is typically coated from an aqueoussuspension formulation. In order to provide a drug coating withsubstantially uniform drug distribution from a suspension formulation,however, the suspension formulation should provide a substantiallyuniform dispersion of the insoluble drug included in the coating.Depending on the relative amounts and nature of the film-forming agentand the one or more drugs included in a drug coating according to thepresent invention, a viscosity enhancer may be included in a drugcoating according to the present invention to facilitate the creation ofa coating formulation that exhibits sufficient viscosity to provide asubstantially uniform drug dispersion and facilitates the production ofa drug coating according to the present invention having a substantiallyuniform distribution of insoluble drug. A viscosity enhancer included ina drug coating according to the present invention is preferablywater-soluble and can be a film-forming agent. Examples of viscosityenhancers that may be used in a drug coating according to the presentinvention include, but are not limited to, HPC (e.g., Klucel®), HEC(e.g., Natrasol®), Polyox® water soluble resin products, andcombinations thereof.

The precise amount of viscosity enhancing material included in a drugcoating according to the present invention will vary, depending on theamounts and type of film-forming polymer and drug materials to be usedin the drug coating. However, where included in a drug coating accordingto the present invention, a viscosity enhancer will typically accountfor 5 wt %, or less, of the drug coating. Preferably, a drug coatingaccording to the present invention includes 2 wt %, or less, viscosityenhancer, and in particularly preferred embodiments, the drug coatingaccording to the present invention includes 1 wt %, or less, viscosityenhancer.

The drug coating of the present invention may also include adisintegrating agent that increases the rate at which the drug coatingdisintegrates after administration. Because the drug coating of thepresent invention typically includes a large amount of insoluble drug,the drug coating may not break down or disintegrate as rapidly asdesired after administration. A disintegrating agent included in acoating according to the present invention is a water swellable materialthat works to structurally compromise the coating as the disintegratingagent absorbs water and swells. Disintegrating agents that may be usedin a drug coating according to the present invention include, but arenot limited to modified starches, modified cellulose, and cross-linkedpolyvinylpyrrolidone materials. Specific examples of disintegratingagents that may be used in the drug coating of the present invention andare commercially available include Ac-Di-Sol®, Avicel®, and PVP XL-10.Where included in a drug coating according to the present invention, adisintegrating agent typically accounts for up to about 6 wt % of thecoating, with coatings incorporating from about 0.5 wt % to about 3 wt %being preferred and coatings incorporating from about 1 wt % to about 3wt % being particularly preferred.

The drug coating according to the present invention may also include asurfactant to increase the rate at which the drug coating dissolves orerodes after administration. The surfactant serves as a “wetting” agentthat allows aqueous liquids to more easily spread across or penetratethe drug coating. Surfactants suitable for use in a drug coatingaccording to the present invention are preferably solid at 25° C.Examples of surfactants that may be used in a drug coating of thepresent invention include, but are not limited to, surface activepolymers, such as Poloxamer and Pluronic® surfactants. Where asurfactant is included in a drug coating according to the presentinvention, the surfactant will typically account for up to about 6 wt %of the drug coating, with drug coatings including about 0.5 wt % toabout 3 wt % surfactant being preferred, and drug coatings includingabout 1 wt % to about 3 wt % surfactant being particularly preferred.

In one embodiment of the drug coating of the present invention, thefilm-forming agent includes a polymer blend formed of copovidone andHPMC. Where such a polymer blend is used as the film-forming agent ofthe drug coating of the present invention, the amounts of copovidone andHPMC may vary, as desired, to achieve a drug coating having desiredphysical and drug-loading characteristics. However, where the film-agentincluded in a drug coating according to the present invention is formedof a blend of copovidone and HPMC, the copovidone and HPMC arepreferably included at a wt/wt ratio about 0.6:1 to about 0.7:1copovidone to HPMC, with a wt/wt ratio of 1:1.5 being most preferred.Blends of HPMC and copovidone provide drug coatings that areaesthetically pleasing and are believed to be sufficiently robust towithstand further processing and an extended shelf life. Moreover, it isbelieved that copovidone can work to solubilize insoluble drug includedin a drug coating according to the present invention, providing a drugcoating that includes a solid solution of insoluble drug.

In another embodiment, the drug coating of the present inventionincludes a blend of HPMC and copovidone as the film-forming agent, and anon-steroidal anti-inflammatory drug (NSAID) as an insoluble drug.NSAIDs that may be included in a drug coating according to the presentinvention include, but are not limited to, ibuprofen, acetaminophen andnaproxen. NSAIDs are widely used as analgesics, anti-inflammatories, andanti-pyretics, and such compounds can be combined with a variety ofdifferent soluble drugs to obtain multi-symptom relief from a variety ofdifferent ailments. For example, a drug coating according to the presentembodiment may include an NSAID in combination with one or more solubleanalgesics, antihistamines or antitussive, or antinausea agents.

In yet another embodiment, the drug coating of the present inventionincludes a blend of HPMC and copovidone as the film-forming agent, aninsoluble NSAID, and a soluble narcotic drug, such as an opiate oropioid drug. In a specific example of such an embodiment, the drugcoating includes an opioid drug, such as hydrocodone. A dosage form thatincludes the combination of acetaminophen or ibuprofen with an opiate oropioid drug provides a combination of analgesic, anti-inflammatory,anti-pyretic, and antitussive actions.

In even further embodiments, a drug coating according to the presentinvention includes a blend of HPMC and copovidone as the film-formingagent, an insoluble NSAID, a soluble narcotic drug, such as an opiate oropioid drug, and a viscosity enhancing agent or a disintegrating agent.In a specific example of such an embodiment, the drug coating includesbetween about 1 wt % and about 2 wt % of a viscosity enhancing agent,such as HPC. In another example of such an embodiment, the drug coatingincludes between about 0.5 wt % and about 3 wt % disintegrating agent,and in yet another example of such an embodiment, the drug coatingincludes between about 0.5 wt % and about 3 wt % of a surfactant.

A drug coating according to the present invention is not only capable ofachieving high drug loading, but where the drug coating according to thepresent invention includes two or more different drugs, it has beenfound that a drug coating according to the present invention providesreleases the different drugs in amounts that are directly proportionalto the amounts of the drugs included in the drug coating. This is trueeven where drugs exhibiting drastically different solubilitycharacteristics, such as acetaminophen and hydrocodone bitartrate (HBH),are included in the drug coating. In addition a drug coating accordingto the present invention releases substantially all of the drug includedtherein. Such performance characteristics facilitate reliable andpredictable drug delivery performance, and allow formulation of drugcoatings according to the present invention that deliver two or moredrugs at a wide range of different ratios.

In another aspect, the present invention is directed to a coatingformulation. A coating formulation according to the present inventioncan be used to provide a drug coating according to the presentinvention. The coating suspension of the present invention includes thematerials used to form a drug coating of the present invention dissolvedor suspended, depending on the material, within one or more solvents orsolutions. The one or more solvents included in a coating suspensionaccording to the present invention are not organic solvents, and arepreferably aqueous solvents. Aqueous solvents that may be used in acoating suspension according to the present invention include, but arenot limited to, purified water, pH adjusted water, acidified water, oraqueous buffer solutions. In a preferred embodiment, the aqueous solventincluded in a coating suspension according to the present invention ispurified water USP. The coating formulation of the present invention,therefore, is preferably an aqueous formulation and avoids the potentialproblems and disadvantages that can result from the use of organicsolvents in formulating coating compositions.

As a drug coating according to the present invention includes at leastone insoluble drug, the coating formulation of the present invention istypically prepared as an aqueous suspension using any suitable process,and in preferred embodiments the coating formulation of the presentinvention is formulated to facilitate production of drug coatingsaccording to the present invention through a known coating process, suchas, for example, known pan coating, fluid bed coating, or any otherstandard coating processes suitable for providing a drug coating. Thoughthe precise amount of solvent used in a coating suspension according tothe present invention may vary depending on, for example, the materialsto be included in the finished drug coating, the desired coatingperformance of the coating suspension and the desired physicalcharacteristics of the finished drug coating, a coating suspensionaccording to the present invention typically includes up to about 30 wt% solids content, with the remainder of the coating suspensionconsisting of the desired solvent. A preferred embodiment of a coatingsuspension of the present invention includes about 80 wt % of a desiredaqueous solvent and about 20 wt % solids content. The coating suspensionof the present invention is formulated to exhibit a viscosity that islow enough to facilitate spray coating of drug coating according to thepresent invention, yet is high enough to maintain a substantiallyuniform dispersion of the insoluble drug included in the coatingsuspension during a coating process.

Because a coating formulation of the present invention is used to createa drug coating according to the present invention, the solids includedin a coating suspension include materials useful in forming a drugcoating according to the present invention. Therefore, the solidsincluded in a coating suspension according to the present inventioninclude at least one insoluble drug and a film-forming agent. The solidsincluded in a coating suspension according to the present invention mayalso include a viscosity enhancer, a surfactant, or a disintegratingagent. As is true of a drug coating according to the present invention,a coating suspension according to the present invention may include twoor more insoluble drugs or one or more insoluble drugs in combinationwith one or more soluble drugs.

In preparing a coating formulation according to the present invention,the drug loaded into the coating formulation may be provided inmicronized form. By reducing the particle size of the drug loaded into acoating formulation according to the present invention, a morecosmetically smooth drug coating may be achieved. In addition, byreducing the particle size of the drug material loaded into a coatingformulation according to the present invention, the dissolution rate ofthe drug when released from the drug coating prepared by the coatingformulation may be improved, particularly where the drug is an insolubledrug. In one embodiment of the coating formulation of the presentinvention, the coating formulation includes a micronized drug materialexhibiting an average particle size of less than 100 microns. In anotherembodiment, the coating formulation of the present invention includes amicronized drug material exhibiting an average particle size of lessthan 50 microns, and in yet another embodiment, the coating formulationof the present invention includes a micronized drug material exhibitingan average particle size of less than 10 microns. Micronization of thedrug material can be readily achieved through processes well known inthe art, such as, for example, known bead milling, jet milling ormicroprecipitation processes, and particle size can be measured usingany conventional particle size measuring technique, such assedimentation field flow fractionation, photon correlation spectroscopyor disk cetrifugation.

The solids dissolved or suspended in a coating formulation according tothe present invention are loaded into the coating formulation in thesame relative amounts as are used in a drug coating according to thepresent invention. For example, the drug included in a coatingformulation of the present invention accounts for about 85 wt % to about97 wt % of the solids loaded into the coating formulation. In preferredembodiments, the drug included in a coating formulation of the presentinvention accounts for about 90 wt % to about 93 wt % of the solidsloaded into the coating formulation. The film-forming agent included ina coating formulation of the present invention accounts for about 3 wt %to about 15 wt % of the solids loaded into the coating formulation, andin preferred embodiments, the film-forming agent included in a coatingformulation of the present invention accounts for about 7 wt % to about10 wt % of the solids loaded into the coating formulation. Whereincluded, a viscosity enhancer will typically account for 5 wt %, orless, of the solids included in a coating formulation of the presentinvention. Coating formulations wherein the viscosity enhancer accountsfor 2 wt %, or less, of the solids are preferred, and in particularlypreferred embodiments, a viscosity enhancer included in a coatingformulation of the present invention accounts for 1 wt %, or less, ofthe solids included in the coating formulation. If the coating to beformed by the coating formulation is to include a disintegrating agent,the disintegrating agent typically accounts for up to about 6 wt % ofthe solids included in the coating formulation. In preferredembodiments, a disintegrating agent will account for about 0.5 wt % toabout 3 wt % of the solids included in the coating formulation, and inparticularly preferred embodiments of a coating formulation including adisintegrating agent, the disintegrating agent accounts for about 1 wt %to about 3 wt % of the solids included in the coating formulation. Wherea surfactant is included in a drug coating according to the presentinvention, the surfactant will typically account for up to about 6 wt %of the solids included in the coating formulation. Preferably, if asurfactant is included in a coating formulation of the presentinvention, the surfactant will account for about 0.5 wt % to about 3 wt% of the solids included in the coating formulation, and in particularlypreferred embodiments of a coating formulation according to the presentinvention that includes a surfactant, the surfactant accounts for about1 wt % to about 3 wt % of the solids included in the coatingformulation.

In yet another aspect, the present invention is directed to a dosageform. A dosage form according to the present invention includes a corecoated by a drug coating according to the present invention. The coreincluded in a dosage form according to the present invention can take ona variety of forms and may be formulated to include one or drugs to bedelivered after dissolution or degradation of the drug coating. Wherethe core of a dosage form includes one or more drugs, such drugs may bethe same as or different from the one or more drugs included in the drugcoating. Such flexibility in the design and formulation of the dosageform of the present invention facilitates the creation of dosage formscapable of delivering a wide range of drugs or combinations of drugs toachieve a variety of different therapeutic results.

In one embodiment, the core included in a dosage form according to thepresent invention may be a pill, particle, pellet, bead, or spheroid,such as nu pareil beads (collectively referred to simply as “pills”). Apill used as a core in a dosage form of the present invention may beformed of a variety of different materials. Moreover, where the dosageform of the present invention includes a core formed by a pill, the pillmay be formulated to be free of active agent or to include one or moreactive agents, as desired. Materials useful for forming a pill to beused as a core in a dosage form of the present invention include, butare not limited to, polymer materials, such as plastic resins, inorganicsubstances, such as silica, glass, hydroxyapatite, salts (e.g., sodiumor potassium chloride, calcium or magnesium carbonate) and the like,organic substances, such as activated carbon, acids (e.g., citric acid,fumaric acid, tartaric acid, or ascorbic acid) and the like, andsaccharides and derivatives thereof. Particularly suitable materials forforming a pill for use as a core in a dosage form of the presentinvention include saccharides such as sugars, oligosaccharides,polysaccharides and their derivatives, such as glucose, rhamnose,galactose, lactose, sucrose, mannitol, sorbitol, destrin, maltodextrin,cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose,starches (e.g., corn starch, rice starch, potato starch, wheat starch,or tapioca starch) and the like. Generally, the core forming materialsdiscussed herein may be used to form pills that are either free from ofdrug or include one or more soluble or insoluble drugs, as desired.

In another embodiment, the dosage form of the present invention includesa core formed using a tablet or capsule. The tablet or capsule includedin such an embodiment can take on virtually any desired size or shapeand may be manufactured using a wide range of known materials. However,where the core of the dosage form of the present invention includes atablet or capsule, the table or capsule is preferably manufactured ofmaterials that are suitable for oral delivery to a desired animal orhuman subject and tablet or capsule is preferably sized and shaped tofacilitate oral delivery. For example, where the core includes a softcapsule or “soft-cap” and the dosage form is intended for oral deliveryto a human subject, the soft-cap preferably exhibits a size ranging fromabout 3 to about 22 minims, with 1 minim being equal to 0.0616 ml, andthe soft-cap may be provided, for example, in standard oval or oblongshapes. In yet another example, where the core of a dosage form of thepresent invention includes a hard capsule or “hard-cap” and is intendedfor oral delivery to human subject, the hard-cap is preferably providedin one of the various standard sizes designated as (000), (00), (0),(1), (2), (3), (4), and (5). Although capsules and tablets exhibitingstandard shapes and sizes are presently preferred due to their readycommercial availability, the core of a dosage form of the present can beformed using tablets or capsules of non-standard size or shape suited toa desired delivery application.

Further, where a dosage form according to the present invention includesa core formed using a tablet or capsule, the tablet or capsule includedin the core is preferably formulated or configured to provide acontrolled release dosage form. The subsequent coating of such a corewith a drug coating according to the present invention formulated toprovide the immediate release of one or more drugs provides a dosageform exhibiting the performance advantages of both an immediate releasedosage form and a controlled release dosage form. Controlled releasedosage forms that may be used to form the core of a dosage form of thepresent invention include, but are not limited to, dosage forms wellknown in the art, such as controlled release dosage forms that include atableted matrix, controlled release matrix dosage forms that include atableted matrix and are banded with one or more insoluble bands toprovided controlled release, and osmotically driven dosage forms.Examples of controlled release dosage forms that may serve as a core ofa dosage form of the present invention include, but are not limited to,the dosage forms described in U.S. Pat. Nos. 4,235,236, 4,278,087,4,663,149, 4,777,049, 4,801,461, 4,854,470, 4,961,932, 5,023,088,5,030,456, 5,221,536, 5,245,357, 5,512,299, 5,534,263, 5,614,578,5,667,804, 5,830,502, 5,858,407, 5,906,832, 5,948,747, 6,020,000,6,153,678, 6,174,547, 6,183,466, 6,245,357, 6,316,028, and 6,365,183;U.S. Patent Publications numbered US2003-0198619, US2003-0232078, andUS2002-0071863; PCT Publications numbered WO 95/34285 and WO 04/02448;and PCT Application numbered US04/24921 (not yet published), thecontents of each of which are incorporated herein in their entirety byreference.

The drug coating included in a dosage form of the present invention canbe formed over the core included in the dosage form using coatingprocesses known in the art. Moreover, a drug coating included in adosage form of the invention can be formed using a coating formulationas described herein. Suitable processes for creating a drug coating in adosage form of the present invention include any standard coatingprocess suitable for providing a drug coating and include, but are notlimited to, known pan coating and fluid bed coating processes.

Though the dosage form of the present invention includes a core coatedby a drug coating according the present invention, the drug coating isnot necessarily the outermost coating of the dosage form. For example,where desired, the drug coating included in a dosage form according tothe present invention may be coated with a color coat or another finishcoat to provide a final dosage form. Alternatively, a drug coatingincluded in a dosage form of the present invention could be coated withanother drug coating, or even a coating designed to cause dissolution ordegradation of the drug coating at a specified location within thegastrointestinal tract of an intended subject, such as an entericcoating, or at a desired time post-administration. Moreover, even thoughthe drug coating included in a dosage form according to the presentinvention is provided over a core, the drug coating need not beimmediately adjacent the core. Regardless of whether the core is formedusing a pill, a tablet, or a capsule, one or more material layers mayintervene between the drug coating and the core-forming material orstructure. Such intervening layers may be included to facilitate betterfunction of either the core forming material or the drug coating.Alternatively, intervening material layers may ease production of thedrug coating or, where desirable, prevent interaction between the coreand the drug composition.

EXAMPLE 1

A drug coating according to the present invention was provided overplacebo dosage forms. The coating included 7.2 wt % film-forming agentformed of a blend of HPMC E5 (supplied by Dow) and copovidone (Kollidon®VA 64, supplied by BASF). The HPMC accounted for 4.3 wt % of the drugcoating, and the Kollidon® VA 64 accounted for 2.9 wt % of the drugcoating. Ibuprofen USP was the drug included in the drug coating, andthe ibuprofen USP accounted for 92.8 wt % of the drug coating.

In order to form the drug coating, an aqueous coating formulation wascreated using purified water USP as the solvent. The coating formulationincluded a solids content of 24 wt % and a solvent content of 76 wt %.The solids loaded into the coating formulation were those that formedthe finished drug coating, and the solids were loaded in the coatingformulation in the same relative proportions as contained in thefinished drug coating. The coating formulation was mixed using standardprocedures to achieve a substantially uniform coating formulation. Thecoating formulation was prepared as a 2,977.5 gram batch.

After forming the coating formulation, the drug coating was formed overthe placebo dosage forms using a Vector LDCS pan coater. The pumpincluded in the coater was a Masterflex® peristaltic pump and the tubingused in the coater was Masterflex® 96410-16 tubing. The pan of thecoater was charged with 1,800 g of the coating formulation, and the drugcoating was coated over the placebo dosage forms under the conditionslisted in Table 1. The placebo dosage forms were processed in the coaterfor 4.5 hours, resulting in the placebo dosage forms being coated with adrug coating weighing about 165 mg, on average.

TABLE 1 Coating Conditions Pan Speed: 21 RPM Atom. Air Pressure: 19 psiGun-to-Bed Dist: 3.5″ Flow Rate: 12 g/min Nozzle: 60100SS Air Cap: 120SSExhaust Temp: 35° C.-45° C. Pan Air Flow: 35-36 CFM

EXAMPLE 2

A drug coating according to the present invention was provided overplacebo dosage forms. The coating included 17.8 wt % film-forming agentformed of a blend of HPMC E5 (supplied by Dow) and copovidone (Kollidon®VA 64, supplied by BASF). The HPMC accounted for 10.7 wt % of the drugcoating and the Kollidon® VA 64 accounted for 7.1 wt % of the drugcoating. The drug included in the coating was ibuprofen USP, and theibuprofen USP accounted for 82.2 wt % of the drug coating.

In order to form the drug coating, an aqueous coating formulation wascreated using purified water USP as the solvent. The coating formulationincluded a solids content of 20 wt % and a solvent content of 80 wt %.The solids loaded into the coating formulation were those that formedthe finished drug coating, and the solids were loaded in the coatingformulation in the same relative proportions as contained in thefinished drug coating. The coating formulation was mixed using standardprocedures to achieve a substantially uniform coating formulation. Thecoating formulation was prepared as a 3978.4 gram batch.

After forming the coating formulation, the drug coating was providedover the placebo dosage forms using a Vector LDCS pan coater. The pumpincluded in the coater was a Masterflex® peristaltic pump and the tubingused in the coater was Masterflex® 96410-16 tubing. The pan of thecoater was charged with 1,800 g of the coating formulation, and the drugcoating was coated over the placebo dosage forms under the conditionslisted in Table 1. The placebo dosage forms were processed in the coaterfor 4.8 hours, resulting in the placebo dosage forms being coated with adrug coating weighing about 188 mg, on average.

EXAMPLE 3

A drug coating according to the present invention was provided overplacebo dosage forms. The coating included 6.0 wt % film-forming agentformed of a blend of HPMC E5 (supplied by Dow) and copovidone (Kollidon®VA 64, supplied by BASF). The HPMC accounted for 3.6 wt % of the drugcoating and the Kollidon® VA 64 accounts for 2.4 wt % of the drugcoating. The drug coating also included HPC (Klucel® MF) as a viscosityenhancer. The HPC accounted for 1.5 wt % of the drug coating. The drugincluded in the drug coating was acetaminophen USP (APAP USP, suppliedby BASF as a fine powder), and the APAP USP accounted for 92.5 wt % ofthe drug coating.

In order to form the drug coating, an aqueous coating formulation wasprepared using purified water USP as the solvent. The coatingformulation included a solids content of 20 wt % and a solvent contentof 80 wt %. The solids loaded into the coating formulation were thosethat formed the finished drug coating, and the solids were loaded in thecoating formulation in the same relative proportions as included in thefinished drug coating. The coating formulation was mixed using standardprocedures to achieve a substantially uniform coating formulation.

The drug coating was formed over the placebo dosage forms using a VectorLDCS pan coater. The pump included in the coater was a Masterflex®peristaltic pump, and the tubing used in the coater was Masterflex®96410-16 tubing. The pan of the coater was charged with 1,800 g of thecoating formulation, and the drug coating was coated over the dosageforms under the conditions listed in Table 1. The placebo dosage formswere processed in the coater for 3.75 hours, resulting in the placebodosage forms being coated with a drug coating weighing about 183 mg, onaverage.

EXAMPLE 4

A drug coating according to the present invention was provided overplacebo dosage forms. The coating included 6.6 wt % film-forming agentformed of a blend of HPMC E5 (supplied by Dow) and copovidone (Kollidon®VA 64, supplied by BASF). The HPMC accounted for 3.95 wt % of the drugcoating and the Kollidon® VA 64 accounted for 2.65 wt % of the drugcoating. The drug coating also included HPC (Klucel® MF) as a viscosityenhancer. The HPC accounted for 1.0 wt % of the drug coating. Aninsoluble drug and a soluble drug were included in the drug coating,with the two drugs accounting for 92.4 wt % of the drug coating. Theinsoluble drug included in the coating was APAP USP (supplied by BASF asa fine powder), which accounted for 90 wt % of the drug coating, and thesoluble drug included in the coating was hydrocodone bitartrate (HBH),which accounted for 2.4 wt % of the drug coating.

In order to form the drug coating, an aqueous coating formulation wascreated using purified water USP as the solvent. The coating formulationincluded a solids content of 20 wt % and a solvent content of 80 wt %.The solids loaded into the coating formulation were those that formedthe finished drug coating, and the solids were loaded in the coatingformulation in the same relative proportions as contained in thefinished drug coating. The coating formulation was mixed using theprocedure outlined in Table 3 to obtain a substantially uniform coatingformulation. The coating formulation was prepared as a 4,000 gram batch.

After forming the coating formulation, the drug coating was providedover the placebo dosage forms using a Vector LDCS pan coater. The pumpincluded in the coater was a Masterflex® peristaltic pump and the tubingused in the coater was Masterflex® 96410-16 tubing. The pan of thecoater was charged with 1,800 g of the coating formulation, and the drugcoating was coated over the placebo dosage forms under the conditionslisted in Table 1 until a coating of about 200 mg (average coatingweight of 199.7 mg) was achieved.

TABLE 3 Coating Formulation Preparation Vessel I Tare the Vessel andturn mixer on. Charge ⅓ water into the vessel. While mixing, slowlycharge the HPC into the vessel. Continue mixing until the material istotally dissolved. Vessel II Tare the vessel, charge ¾ of water requiredinto the vessel. While mixing, slowly charge the Copovidone into thevessel. Continue mixing until the material is dissolved. While mixing,slowly charge the HPMC into the vessel. Continue mixing until thematerial is dissolved. Transfer the Vessel I solution into the VesselII. Mix until a clear solution results. If including a disintegrant or asurfactant, add disintegrant or surfactant while mixing. Mix until thesolution is homogeneous. While mixing, slowly charge the insoluble drug(e.g., APAP or ibuprofen) into the mixing vessel. Continue mixing untilno lumps are present. Mix for at least two hours before use. Determinethe net amount of drug coating formulation prepared. Continue mixinguntil the required amount of drug coating formulation is applied. Do notallow a vortex to form.

EXAMPLE 5

The dissolution rates of both APAP and HBH from the drug coatingprepared according to Example 4 was evaluated and compared with thedissolution rates provided by Vicodin® tablets. USP Type II equipmentwas used to evaluate the dissolution rates from the exemplary drugcoating and from the Vicodin® tablets. As can be seen by reference toFIG. 1 and FIG. 2, the dissolution rates of both APAP and HBH from theexemplary drug overcoat were comparable to those provided by theVicodin® tablets, with the t₉₀ of the APAP and HBH from the exemplarydrug coating and from the Vicodin® tablets occurring within 30 minutes.

EXAMPLE 6

The dissolution profiles of APAP and HBH from drug coatings according tothe present invention were evaluated based on mass balance. The targetrelease ratio of APAP:HBH from the drug coating was 34:1. Threedifferent lots of dosage forms having coatings according to presentinvention were evaluated. The results of such evaluation are provided inFIG. 3, and as can be seen from FIG. 3, the drug coatings according tothe present invention provided desirable APAP and HBH releaseperformance, with the drug coatings in each lot releasing the APAP andHBH at or very near the targeted release ratio.

EXAMPLE 7

The dissolution rates of APAP from four different drug coatingsaccording to the present invention were compared to the dissolution rateof APAP from a commercially available NORCO® tablet. The formulations ofeach of the four different drug coatings are provided in Table 2. HBHwas included in Table 2 for calculation purposes only. The HBH was notincluded in any of the four coating formulations prepared in thisExample.

In order to form each of the four different drug coatings, fourdifferent aqueous coating formulations were prepared using purifiedwater USP as the solvent. Each of the four coating formulations includeda solids content of 20 wt % and a solvent content of 80 wt %. Each ofthe four coating formulations was loaded with the solids used to formone of the four different coating formulations. The coating formulationswere mixed using procedure outlined in Table 3 to achieve substantiallyuniform coating formulations.

After forming the coating formulations, the four drug coatings wereprovided over the placebo dosage forms using a Vector LDCS pan coater.The pump included in the coater was a Masterflex® peristaltic pump andthe tubing used in the coater was Masterflex® 96410-16 tubing. Duringeach coating process, the pan of the coater was charged with 1,800 g ofthe desired coating formulation. The four different drug coatings werecoated over the placebo dosage forms under the conditions listed inTable 1 until coatings provided the average weight gains detailed inTable 2.

In order to evaluate the dissolution rate of APAP from each of the fourdifferent coatings and from the NORCO® tablet, a USP Type II apparatuswas used. The media used was 900 ml of acidified water maintained at 37°C., and the stir rate was 50 rpm. The amount of APAP present in themedia was measured at 5-minute intervals over a period of 90 minutesusing a standard UV assay technique.

The results of the dissolution testing are shown in FIG. 4 and FIG. 5.As can be seen by reference to FIG. 4 and FIG. 5, the inclusion of asurfactant or a disintegrating agent in a drug coating according to thepresent invention can provide measurable improvements in the rate atwhich drug is released from the drug coating. In the case of thedisintegrating agent Ac-Di-Sol®, increasing the amount of Ac-Di-Sol® inthe drug coating can provide an increase in the rate at which drug isdissolved from the coating, with the drug coating that includes 3.0 wt %Ac-Di-Sol® providing a dissolution rate approaching that provided by theNORCO® tablet.

TABLE 2 Drug Overcoat Formulations (Example 7) Formulation (wt %) NoSufactant/ 1.5% 3.0% Materials Code No Disintegrant DisentegrantSurfactant Disentegrant APAP 0012590 90.00 90.00 90.00 88.00 HBC 00113342.40 2.40 2.40 2.40 (For Calculation Purposes Only) Copovidone 00114452.65 2.04 2.04 2.24 HPMC 2910 0001634 3.95 3.06 3.06 3.36 HPC 00006141.00 1.00 1.00 1.00 Ac-Di-Sol 80142 — 1.50 — 3.00 Poloxamer 188 4304 — —1.50 — Weight Gain 199.7 196.7 194.4 196.6 Total APAPDose 180 177 175173

EXAMPLE 8

A drug coating according to the present invention including a surfactantwas formed over placebo dosage forms. The coating included 5.1 wt %film-forming agent formed of a blend of HPMC 2910 and copovidone(Kollidon® VA 64, supplied by BASF). The HPMC accounted for 3.06 wt % ofthe drug coating and the Kollidon® VA 64 accounted for 2.04 wt % of thedrug coating. The drug coating also included HPC (Klucel® MF) as aviscosity enhancer, and Poloxamer 188 as a surfactant. The HPC accountedfor 1.0 wt % of the drug coating, and the Poloxamer accounted for 1.5 wt% of the drug coating. An insoluble drug and a soluble drug wereincluded in the drug coating, with the two drugs accounting for 92.4 wt% of the drug coating. The insoluble drug included in the coating wasAPAP USP (supplied by BASF as a fine powder), which accounted for 90 wt% of the drug coating, and the soluble drug included in the coating wasHBH, which accounted for 2.4 wt % of the drug coating.

In order to form the drug coating, an aqueous coating formulation wascreated using purified water USP as the solvent. The coating formulationincluded a solids content of 20 wt % and a solvent content of 80 wt %.The solids loaded into the coating formulation were those that formedthe finished drug coating, and the solids were loaded in the coatingformulation in the same relative proportions as contained in thefinished drug coating. The coating formulation was mixed using theprocedure outlined in Table 3 to achieve a substantially uniform coatingformulation.

After forming the coating formulation, the drug coating was providedover the placebo dosage forms using a Vector LDCS pan coater. The pumpincluded in the coater was a Masterflex® peristaltic pump and the tubingused in the coater was Masterflex® 96410-16 tubing. The pan of thecoater was charged with 1,800 g of the coating formulation, and the drugcoating was coated over the placebo dosage forms under the conditionslisted in Table 1 until a drug coating of about 200 mg (average coatingweight of 194.4 mg) was achieved.

EXAMPLE 9

A drug coating according to the present invention including adisintegrating agent was formed over placebo dosage forms. The coatingincluded 5.1 wt % film-forming agent formed of a blend of HPMC 2910 andcopovidone (Kollidon® VA 64, supplied by BASF). The HPMC accounted for3.06 wt % of the drug coating and the Kollidon® VA 64 accounted for 2.04wt % of the drug coating. The drug coating also included HPC (Klucel®MF) as a viscosity enhancer, and Ac-Di-Sol® as a disintegrating agent.The HPC accounted for 1.0 wt % of the drug coating, and the Ac-Di-Sol®accounted for 1.5 wt % of the drug coating. An insoluble drug and asoluble drug were included in the drug coating, with the two drugsaccounting for 92.4 wt % of the drug coating. The insoluble drugincluded in the coating was APAP USP (supplied by BASF as a finepowder), which accounted for 90 wt % of the drug coating, and thesoluble drug included in the coating was HBH, which accounted for 2.4 wt% of the drug coating.

In order to form the drug coating, an aqueous coating formulation wascreated using purified water USP as the solvent. The coating formulationincluded a solids content of 20 wt % and a solvent content of 80 wt %.The solids loaded into the coating formulation were those that formedthe finished drug coating, and the solids were loaded in the coatingformulation in the same relative proportions as contained in thefinished drug coating. The coating formulation was mixed using theprocedure outlined in Table 3 to achieve a substantially uniform coatingformulation.

After forming the coating formulation, the drug coating was providedover the placebo dosage forms using a Vector LDCS pan coater. The pumpincluded in the coater was a Masterflex® peristaltic pump and the tubingused in the coater was MasterFlex® 96410-16 tubing. The pan of thecoater was charged with 1,800 g of the coating formulation, and the drugcoating was coated over the placebo dosage forms under the conditionslisted in Table 1 until a drug coating of about 200 mg (average coatingweight of 196.7 mg) was achieved.

EXAMPLE 10

A drug coating according to the present invention including adisintegrating agent is prepared and coated onto a dosage form. Thecoating includes 5.6 wt % film-forming agent formed of a blend of HPMC2910 and copovidone (Kollidon® VA 64, supplied by BASF). The HPMCaccounts for 3.36 wt % of the drug coating and the Kollidon® VA 64accounts for 2.24 wt % of the drug coating. The drug coating alsoincludes HPC (Klucel® MF) as a viscosity enhancer, and Ac-Di-Sol® as adisintegrating agent. The HPC accounts for 1.0 wt % of the drug coating,and the Ac-Di-Sol® accounts for 3.0 wt % of the drug coating. Aninsoluble drug and a soluble drug are included in the drug coating, withthe two drugs accounting for 90.4 wt % of the drug coating. Theinsoluble drug included in the coating is APAP USP (supplied by BASF asa fine powder), which accounts for 88.0 wt % of the drug coating, andthe soluble drug included in the coating is HBH, which accounts for 2.4wt % of the drug coating.

An aqueous coating formulation is created using purified water USP asthe solvent. The coating formulation includes a solids content of 20 wt% and a solvent content of 80 wt %. The solids loaded into the coatingformulation are those that form the finished drug coating, and thesolids are loaded in the coating formulation in the same relativeproportions will be exhibited in the finished drug coating. The coatingformulation is mixed using the procedure outlined in Table 3 to achievea substantially uniform coating formulation.

After forming the coating formulation, the drug coating is provided overthe dosage forms using a Vector LDCS pan coater. The pump included inthe coater is any suitable pump, such as a Masterflex® peristaltic pump,and the tubing used in the coater is any suitable tubing, such asMasterflex® 96410-16 tubing. The pan of the coater is charged with adesired amount of the coating formulation, and the drug coating iscoated over the dosage forms under the conditions listed in Table 1until a drug coating of a desired weight is achieved.

EXAMPLE 11

A drug coating according to the present invention is provided over adosage form. The coating includes 7.0 wt % film-forming agent formed ofa blend of HPMC E5 (supplied by Dow) and copovidone (Kollidon®VA 64,supplied by BASF). The HPMC accounts for 4.2 wt % of the drug coating,and the Kollidon® VA 64 accounts for 2.8 wt % of the drug coating. Thedrug coating includes an insoluble drug and a soluble drug, with thetotal drug content of 93 wt %. The insoluble drug included in thecoating is ibuprofen USP, which accounts for 90 wt % of the drugcoating, and the soluble drug included in the coating is HBH, whichaccounts for 3 wt % of the drug coating.

To form the drug coating, an aqueous coating formulation is preparedusing purified water USP as the solvent. The coating formulationincludes a solids content of 25 wt % and a solvent content of 75 wt %.The solids loaded into the coating formulation are those that form thefinished drug coating, and the solids are loaded in the coatingformulation in the same relative proportions as will be exhibited in thefinished drug coating. The coating formulation is mixed using standardprocedures to achieve a substantially uniform coating formulation.

The drug coating is formed over the dosage forms using any suitablecoater, such as a Vector LDCS pan coater. The pump included in thecoater is any suitable pump, such as a Masterflex® peristaltic pump, andthe tubing used in the coater is any suitable tubing, such asMasterflex® 96410-16 tubing. The pan of the coater is charged with adesired amount of the coating formulation, and the drug coating iscoated over the placebo dosage forms under the conditions listed inTable 1 until a drug coating of a desired weight is achieved.

EXAMPLE 12

A drug coating according to the present invention is formed over adosage form. The coating includes 17.3 wt % film-forming agent formed ofa blend of HPMC E5 (supplied by Dow) and copovidone (Kollidon® VA 64,supplied by BASF). The HPMC accounts for 10.4 wt % of the drug coatingand the Kollidon® VA 64 accounts for 6.9 wt % of the drug coating. Thedrug coating includes an insoluble drug and a soluble drug, with thetotal drug content of 82.7 wt %. The insoluble drug included in thecoating is ibuprofen USP, which accounts for 80 wt % of the drugcoating, and the soluble drug included in the coating is HBH, whichaccounts for 2.7 wt % of the drug coating.

To form the drug coating, an aqueous coating formulation is preparedusing purified water USP as the solvent. The coating formulationincludes a solids content of 20 wt % and a solvent content of 80 wt %.The solids loaded into the coating formulation are those that form thefinished drug coating, and the solids are loaded in the coatingformulation in the same relative proportions as will be exhibited in thefinished drug coating. The coating formulation is mixed using standardprocedures to achieve a substantially uniform coating formulation.

The drug coating is provided over the dosage forms using any suitablecoater, such as a Vector LDCS pan coater. The pump included in thecoater is any suitable pump, such as a Masterflex® peristaltic pump, andthe tubing used in the coater is any suitable tubing, such asMasterflex® 96410-16 tubing. The pan of the coater is charged with adesired amount of the coating formulation, and the drug coating iscoated over the dosage forms under the conditions listed in Table 1until a drug coating of a desired weight is achieved.

EXAMPLE 13

A drug coating according to the present invention is provided over adosage form. The coating includes 5.85 wt % film-forming agent formed ofa blend of HPMC E5 (supplied by Dow) and copovidone (Kollidon® VA 64,supplied by BASF). The HPMC accounts for 3.5 wt % of the drug coatingand the Kollidon® VA 64 accounts for 2.35 wt % of the drug coating. Thedrug coating also includes HPC (Klucel® MF) as a viscosity enhancer. TheHPC accounts for 1.5 wt % of the drug coating. An insoluble drug and asoluble drug are included in the drug coating, with the two drugsaccounting for 92.65 wt % of the drug coating. The insoluble drugincluded in the coating is acetaminophen, which accounts for 90 wt % ofthe drug coating, and the soluble drug included in the coating is HBH,which accounts for 2.65 wt % of the drug coating.

In order to form the drug coating, an aqueous coating formulation isprepared using purified water USP as the solvent. The coatingformulation includes a solids content of 20 wt % and a solvent contentof 80 wt %. The solids loaded into the coating formulation are thosethat form the finished drug coating, and the solids are loaded in thecoating formulation in the same relative proportions as will beexhibited in the finished drug coating. The coating formulation is mixedusing the procedure outlined in Table 3 to achieve a substantiallyuniform coating formulation.

The drug coating is formed over the dosage forms using any suitablecoater, such as a Vector LDCS pan coater. The pump included in thecoater is any suitably pump, such as a Masterflex® peristaltic pump, andthe tubing used in the coater may be any suitable tubing, such asMasterflex® 96410-16 tubing. The pan of the coater is charged with adesired amount of the coating formulation, and the drug coating iscoated over the dosage forms under the conditions listed in Table 1until a coating of desired weight is achieved.

1. A dosage form comprising: an osmotic core comprising hydrocodone; acoating comprising acetaminophen, a viscosity enhancer, a water solublefilm former comprising copovidone and hydroxypropyl methylcellulose in awt/wt ratio of between 0.6:1 to 0.7:1, and an excipient selected fromthe group consisting of a surfactant and a disintegrating agent; and anintervening layer between the osmotic core and the coating; wherein theacetaminophen is present in the coating in an amount ranging from about60 wt % to about 97 wt % based on the total weight of the coating, theviscosity enhancer accounts for about 5 wt % or less based on said totalweight, the excipient accounts for about 0.5 wt % to about 3 wt % basedon said total weight, and the water soluble film former accounts forabout 3 wt % to about 15 wt % based on said total weight.
 2. The dosageform of claim 1, wherein acetaminophen is present in the coating in anamount ranging from about 85 wt % to about 97 wt %, based on the totalweight of the coating.
 3. The dosage form of claim 1, wherein theacetaminophen is present in the coating in an amount ranging from about75 wt % to about 89.5 wt %, based on the total weight of the coating. 4.The dosage form of claim 1, wherein the wt/wt ratio of copovidone tohydroxypropyl methylcellulose is about 1:1.5.